Pancreatic ductal adenocarcinoma, PDA, is diagnosed in approximately 30,000 Americans every year. With an overall 5-year survival rate of less than 5% it kills approximately 33,000 Americans a year, making it the fourth leading cause of cancer death. This makes PDA one of the deadliest of all malignancies. Recently increased expression of the Ski protein has been found in a large number of PDA's (approx 70%). This increased expression was associated with a bad prognosis, however the mechanism by which Ski expression leads to a bad prognosis is unclear. Recently we determined that increased expression of Ski results in increased expression of the class I histone deacetylase HDAC3. Increased levels of class 1 HDACs have been found in several human cancers and are associated with bad prognosis and thus the increased level of HDAC3 may well contribute to the bad prognosis of Ski- positive PDA. HDAC inhibitors are in use in the clinic to therapeutically target these enzymes. However there are several drawbacks associated with inhibition of HDACs, since these enzymes play key roles in cell development and homeostasis, and deleterious side effects have been noted in recent clinical trials. Therefore in this proposal we will take a different approach and synthesize drugs that will be activated by class1 HDAC activity. We hypothesize that the increased HDAC3 levels in PDA will provide a therapeutic target for this new class of prodrugs. In this proposal we will test this hypothesis by designing a new class of pro-drugs that are co-activated by HDAC3 activity together with the well- characterized tumor-associated protease activity associated with PDA and determine the effect of these drugs on PDA cell lines in vitro as well as in vivo. These studies will identify HDAC3 as a defined molecular target for future clinical intervention. Our new class of prodrugs that target the increased levels of class 1 HDACs associated with human cancers, including PDA, and due to its two-step activation process will hopefully be more specific for tumor cells and have lower non-specific toxicity and have the potential to provide some help in treating this dreadful disease.